Ma Jun, Yang Jie, Wang Chao, Zhang Nan, Dong Ying, Wang Chengjie, Wang Yu, Lin Xinjian
Department of Obstetrics and Gynecology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200127, China.
Department of Cell Biology, Key Laboratory of the Education Ministry for Cell Differentiation and Apoptosis, Institute of Medical Sciences, School of Medicine, Shanghai Jiaotong University, Shanghai 200025, China.
Biomed Res Int. 2014;2014:107671. doi: 10.1155/2014/107671. Epub 2014 Dec 14.
The intracellular level of reactive oxygen species (ROS) is closely associated with chemosensitivity of cancer cells. Overexpression of ATP binding cassette transporter MRP1 is correlated with resistance to platinum drugs. In this study, we tested the hypothesis that emodin, a potent ROS generator, may increase sensitivity of cisplatin-(cDDP-) resistant ovarian carcinoma cells to cDDP cytotoxicity via ROS-mediated suppression of MRP1 expression. Using the isogenic pair of the human ovarian carcinoma cell line COC1 and its cDDP resistant variant COC1/DDP, we found that ROS level in the cDDP-sensitive ovarian cancer cells was significantly higher than that in the cDDP-resistant cells. Emodin enhanced ROS production in COC1/DDP cells and consequently sensitized them to cDDP-induced apoptosis. These effects were reversed by addition of the antioxidant N-acetyl-L-cysteine (NAC). Cotreatment with emodin and cDDP inhibited the tumor growth in vivo by increasing tumor cell apoptosis. The emodin-enhanced cDDP cytotoxicity was attributable to downregulation of multidrug resistance-related protein 1 (MRP1) expression. Together, these results suggest that emodin could act as an adjunct to enhance the anticancer effect of cDDP likely through ROS-related downregulation of MRP1 expression, and may be of therapeutic potential in cDDP-refractory ovarian carcinomas.
细胞内活性氧（ROS）水平与癌细胞的化疗敏感性密切相关。ATP结合盒转运体MRP1的过表达与对铂类药物的耐药性相关。在本研究中，我们检验了以下假设：大黄素作为一种有效的ROS生成剂，可能通过ROS介导的MRP1表达抑制作用，增加顺铂（cDDP）耐药的卵巢癌细胞对cDDP细胞毒性的敏感性。使用人卵巢癌细胞系COC1及其cDDP耐药变体COC1/DDP的同基因配对，我们发现cDDP敏感的卵巢癌细胞中的ROS水平显著高于cDDP耐药细胞。大黄素增强了COC1/DDP细胞中的ROS生成，从而使它们对cDDP诱导的凋亡敏感。添加抗氧化剂N-乙酰-L-半胱氨酸（NAC）可逆转这些作用。大黄素与cDDP联合处理通过增加肿瘤细胞凋亡抑制了体内肿瘤生长。大黄素增强的cDDP细胞毒性归因于多药耐药相关蛋白1（MRP1）表达的下调。总之，这些结果表明大黄素可能通过与ROS相关的MRP1表达下调，作为增强cDDP抗癌作用的辅助药物，并且在cDDP难治性卵巢癌中可能具有治疗潜力。
